It could be argued that drug discovery strategies of the past were analogous to fishing with a line and hook. A systematic series of trial and error experiments such as quantitative structure-activity relationship (QSAR) methodologies, for example, were commonplace. The process was iterative and labor intensive. A chemist or biologist had relatively few restrictions, particularly with time, to explore ideas and test hypotheses. The overall endeavor was more craft than process.

Today's preference for drug discovery is on high throughput approaches to accelerate the generation, identification, and optimization of molecules with desirable drug properties. A large number of samples and corresponding analytical measurements are required to make quick and confident decisions. Certainly, the need for a faster pace of research is warranted. However, the current strategies that emphasize fast cycle times make it appear that new drug candidates are discovered not with a line and hook approach but harvested with nets. The craft still remains, but it is often difficult to see in the midst of production-scale events.

Fueled by the prospects of a highly efficient drug discovery process and the need for an expanded drug development pipeline, the pharmaceutical industry has aggressively embraced technology over the past decade. Medicinal chemistry has played a central role with the integration of automated synthesis technologies. New drug discovery paradigms were subsequently born and these high throughput medicinal chemistry approaches helped to serve as the gateway for novel biomolecular screening and proteomics techniques. During this time, high throughput screening approaches for drug metabolism and pharmacokinetic characteristics became an essential part of the drug discovery landscape.

The swift integration of highly productive technologies that focused on sample generation created bottlenecks in drug discovery. Simply put, medicinal chemists and their collaborators were generating samples at a faster rate than they were capable of analyzing them. New formats for automated synthesis combined with a faster pace of drug discovery led to a shift in sample analysis requirements from a relatively pure sample type to a trace-mixture. Traditional methods of analysis became antiquated. New analytical strategies and techniques were necessary to meet sample throughput requirements and manpower constraints. Technologies with appropriate sensitivity, selectivity, and speed were quickly integrated into mainstream drug discovery paradigms to effectively handle the predominant sample type, a trace-mixture. Drug discovery was forced to become more dependent on technology and become more agile. Fortunately, scientists became more open about the notion of using mass spectrometry as a front-line tool throughout drug discovery.

This book is based on a special issue of Curr. Top. Med. Chem. published in January 2002. The focus is primarily on mass spectrometry-based applications in drug discovery that require trace-mixture analysis. The selection of topics is not intended to be comprehensive, but rather highlight the creativity of analytical scientists and their collaborators that have led to current standards for analysis in drug discovery. Innovators in the field describe their unique perspectives on integrated strategies for analysis and share future prospects. The topics represent current industry benchmarks in specific drug discovery activities that deal with proteomics, biomarker discovery, metabonomic approaches for toxicity screening, lead identification, compound libraries, quantitative bioan-alytical support, biotransformation, reactive metabolite characterization, lead optimization, pharmaceutical property profiling, sample preparation strategies, and automation.

Interestingly, the traditional definition and core focus of drug discovery is still applicable today. A significant change has been the preference for high throughput approaches and the explosive development of analytical instrumentation that allows for the facile interrogation (qualitative and quantitative) of a trace-mixture. Analytical technologies now provide an integral component for modern drug discovery practices. Similar to the location mantra prescribed in real estate, the fundamental merits of sensitivity are a requisite for high throughput analytical measurements in drug discovery. Due to limited sample quantities and the need to interrogate compounds of interest at low concentration, "sensitivity, sensitivity, sensitivity" will most likely remain as the analytical mantra in drug discovery. However, highly sensitive analytical platforms such as mass spectrometers will continue to benefit from orthogonal techniques such as chromatography, sample preparation, and informatics.

These techniques will enable the analytical scientist to demonstrate control of the analytical method and provide the necessary selectivity, speed, repro-ducibility, and robustness.

It is hoped that this book will provide historical perspective on analytical strategies in drug discovery and illustrate the widened scope of mass spec-trometry applications.

Mike S. Lee

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